Targeting neuronal FTL1 rescues cognitive impairments in aging
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ABSTRACT:
PROVIDER: PRJNA1047170 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:TARGETING NEURONAL FTL1 RESCUES COGNITIVE IMPAIRMENTS IN AGING
| PRJNA1049409 | ENA
Project description:Understanding cellular and molecular drivers of age-related cognitive decline is necessary to identify targets to restore cognition at old age. Here we report that ferritin light chain 1 (FTL1) is a pro-aging neuronal factor that impairs cognition. Targeting neuronal FTL1 in the hippocampi of aged mice elicits synaptic and metabolic-related molecular changes and rescues cognitive impairments. Our data identify neuronal FTL1 as a key molecular mediator of cognitive rejuvenation.
2025-07-08 | GSE249105 | GEO
Project description:Understanding cellular and molecular drivers of age-related cognitive decline is necessary to identify targets to restore cognition at old age. Here we report that ferritin light chain 1 (FTL1) is a pro-aging neuronal factor that impairs cognition. Targeting neuronal FTL1 in the hippocampi of aged mice elicits synaptic and metabolic-related molecular changes and rescues cognitive impairments. Our data identify neuronal FTL1 as a key molecular mediator of cognitive rejuvenation.
2024-12-01 | GSE249504 | GEO
Project description:Endothelin B receptor inhibition rescues aging-dependent neuronal regenerative decline [scRNA-seq]
| PRJNA1269306 | ENA
Project description:Endothelin B receptor inhibition rescues aging-dependent neuronal regenerative decline [snRNA-seq]
| PRJNA1269311 | ENA
Project description:Changes in peripheral CD8+ T cells are a prominent hallmark of immune aging. While infiltrating CD8+ T cells are implicated in aging and neurodegenerative disease-related pathology in the brain, the role of aged non-infiltrating CD8+ T cells has yet to be fully defined. Here, we show that targeting activated aged peripheral CD8+ T cells rescues age-related cognitive decline. Using heterochronic parabiosis and single cell transcriptomics analysis we observed that aged peripheral CD8+ T cells maintain properties intrinsic to their age, being refractory to the effects of a young or aged systemic milieu. Systemic exposure of young mice to aged CD8+ T cells elicited synaptic-related aging transcriptional signatures in the hippocampus and impaired cognition. Inhibiting migration of aged peripheral CD8+ T cells to lymph nodes mitigated pro-aging effects on the young hippocampus. Conversely, targeting aged CD8+ T cells restored synaptic-related signatures in the aged hippocampus and ameliorated cognitive impairments. Mechanistically, we identified granzyme k (GZMK) as a secreted age-associated CD8+ T cell-derived factor that impairs cognitive function. Together, our data identify activated aged CD8+ T cells and their secreted factors as potential therapeutic targets to rescue cognition in old age.
2025-05-02 | GSE266468 | GEO
Project description:Changes in peripheral CD8+ T cells are a prominent hallmark of immune aging. While infiltrating CD8+ T cells are implicated in aging and neurodegenerative disease-related pathology in the brain, the role of aged non-infiltrating CD8+ T cells has yet to be fully defined. Here, we show that targeting activated aged peripheral CD8+ T cells rescues age-related cognitive decline. Using heterochronic parabiosis and single cell transcriptomics analysis we observed that aged peripheral CD8+ T cells maintain properties intrinsic to their age, being refractory to the effects of a young or aged systemic milieu. Systemic exposure of young mice to aged CD8+ T cells elicited synaptic-related aging transcriptional signatures in the hippocampus and impaired cognition. Inhibiting migration of aged peripheral CD8+ T cells to lymph nodes mitigated pro-aging effects on the young hippocampus. Conversely, targeting aged CD8+ T cells restored synaptic-related signatures in the aged hippocampus and ameliorated cognitive impairments. Mechanistically, we identified granzyme k (GZMK) as a secreted age-associated CD8+ T cell-derived factor that impairs cognitive function. Together, our data identify activated aged CD8+ T cells and their secreted factors as potential therapeutic targets to rescue cognition in old age.
2025-05-02 | GSE266467 | GEO
Project description:A central hallmark of brain aging is the alteration of neuronal functions in the hippocampus, leading to a progressive decline in learning and memory. Multiple reports have shown the importance of blood-borne factors in inter-tissue communication for the maintenance of cognitive fitness and proper regulation of neuronal homeostasis throughout life. Among these blood-borne factors, we identified Osteocalcin (OCN), a bone-derived hormone. OCN induces autophagy machinery in hippocampal neurons which is essential for activity-dependent synaptic plasticity. However, the way in which blood-borne factors like OCN communicate with neurons, including their regulatory mechanisms, remains largely elusive. Here, we show the importance of a core primary cilium (PC)-proteins/autophagy machinery axis in hippocampal neurons that mediate the effects of the pro-youthful blood factor OCN on neuronal homeostasis and cognitive fitness. We found that OCN’s receptor, GPR158, is present at the PC of hippocampal neurons and mediates the regulation of autophagy machinery by OCN. During aging, PC-core proteins are reduced in hippocampal neurons and associated with neuronal PC morphological abnormalities. Restoring their levels is sufficient to improve neuronal autophagy and cognitive impairments in aged mice. Mechanistically, we found that OCN promotes neuronal autophagy in the hippocampus by the induction of PC-dependent cAMP response element-binding protein (CREB) signaling pathway. Altogether, this study proposes a novel paradigm for blood factor-neuron communication dependent on a neuronal PC/autophagy axis by identifying a novel regulatory pathway fostering cognitive fitness and providing the foundation for autophagy-based therapeutic strategies to treat age-related cognitive dysfunction.
2024-11-07 | PXD056975 | Pride
Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1β selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1β. Consistent with our findings in mice, selective hypomethylation of IL-1β at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia
2014-10-01 | E-GEOD-56452 | biostudies-arrayexpress
Project description:Components of the proteostasis network malfunction in the aging brain and this reduced neuronal protein quality control has been proposed to increase risk for neurodegeneration. Here, we have focused on chaperone-mediated autophagy (CMA), a selective type of autophagy that contributes to turnover of neurodegeneration-related proteins. We generated mouse models with CMA blockage in dopaminergic or glutamatergic neurons to investigate the physiological role of CMA in neurons in vivo and the consequences of neuronal CMA loss in aging, We found that loss of neuronal CMA leads to behavioral impairments, altered neuronal function, selective changes in the neuronal proteome and proteotoxicity, all reminiscent of brain aging. Furthermore, imposing CMA loss on an experimental mouse model of Alzheimer’s disease, increased neuronal disease vulnerability and accelerated disease progression. We conclude that functional CMA is essential for neuronal proteostasis and that CMA activation could be an efficient disease-modifying therapy in neurodegenerative disorders.
2021-04-23 | PXD017108 | Pride